B. Studies and Results Overview. Throughout the R21 project phase, we developed an IVR platform design that allows for delivery of one or more drugs at controlled rates. The IVRs use a reservoir design, with a core of solid drug (API) coated in multiple polymer layers and embedded in the silicone IVR. The API is released through a delivery window of controlled size. A key aspect was to create an IVR fabrication process that is amenable to GMP IVR production on a scale suitable for clinical trials, and further scalable to produce IVRs in quantities > 10[6] per year. To accomplish this goal, we followed an iterative IVR development process throughout the R21 phase. Initially, as detailed in the original project proposal, solid silicone or EVA IVRs were obtained commercially, and API reservoirs and delivery windows were created by milling the silicone. This worked as a proof-of-concept, but the process was modified incrementally to yield the current IVR production process. A. Specific Aims The broad long term goal of this project is to empower women to protect themselves from HIV infection through the development of improved vaginal ring microbicide formulations based on a sustained release drug delivery platform that will allow for the use of multiple agents. The specific aims of the first two year's proposed efforts (R21) were modified from the original competing application at the request of the program officer and SRG to remove in vivo studies and focus exclusively on the development of a tenofovir sustained release intravaginal ring (IVR) platform and evaluation of its in vitro release characteristics. The first milestone of the R21 was to produce silicone IVRs delivering 4010 pg/day TFV (tenofovir, PMPA) and IVRs delivering 4010 Mg/day Viread (tenofovir disoproxil fumarate, TDF). The second milestone is to then develop IVRs delivering each drug at 0.5 and 1 log unit above milestone 1 levels (12020 Mg/day and 40050 [ig/day).